Antibodies (Abs) with innate proteolytic activity are detected in the mouse and human autoimmune repertoires. Antibodies in human SLE and in a murine lupus model (MRL/lpr) have also been shown to bind HIV-1 antigens with high affinity. The central hypothesis of this proposal is that specific catalytic Abs against HIV-1 gp120 could be expressed in subjects with autoimmune disease. Such antibodies may have therapeutic potential for inactivation of HIV-1 infectivity through specific proteolysis at viral capsid sites. Molecular studies suggest that a serine protease-like active site at or near the antigen binding site of peptidase Abs is encoded by a germline VL gene. Our proposal will explore the occurrence, molecular specificity and biological activity of HIV- 1 gp120-specific Ab proteases that arise in autoimmunity. A variable domain (Fv)-phage library, constructed from antibody genes found in human SLE is expected to comprise both catalytic and gp120-specific antibodies. Proteolytic Ab fragments from the phage display libraries will be obtained by chemical selection, using active site-modifying reagents for specific covalent labeling and affinity capture of Abs with serine protease-like reactivity. A series of reagents having a common reactive group and differing degrees of analogy with the target substrate (gp120) will be compared for their relative efficacy in capturing specific and catalytically efficient Abs from the library. These studies will also examine if proteolytic degradation at specific gp120 sites, including a neutralizing epitope for conventional antibodies leads to more effective inactivation of the virus. The range of binding specificities in the lupus repertoire suggests that broadly inactivating catalytic Abs are likely to be identified. Insights from the mechanistic studies shall be integrated into the studies of the comparison proposals of the program project application. The overall Program Project has significant implications for development of a new therapeutic modality for treatment or prevention of HIV infection.